Not applicable.
Not Applicable
1. Field of the Invention
The present invention pertains to methods and pharmaceutical compositions for using the selegiline metabolite R(xe2x88x92) desmethylselegiline (also referred to simply as xe2x80x9cdesmethylselegilinexe2x80x9d or xe2x80x9cR(xe2x88x92)DMSxe2x80x9d) alone; its enantiomer ent-desmethylselegiline (also referred to as xe2x80x9cS(+)desmethylselegilinexe2x80x9d or xe2x80x9cS(+)DMSxe2x80x9d) alone; or a combination, such as, for example, a racemic mixture, of the two enantiomers. In particular, the present invention provides compositions and methods for using these agents in the treatment of selegiline-responsive diseases and conditions, particularly diseases or conditions involving neoplastic cells, such as cancerous cells, or those cells that proliferate for no physiologically advantageous purpose.
2. Description of Related Art
Two distinct monoamine oxidase enzymes are known in the art: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). The cDNAs encoding these enzymes show different promoter regions and distinct exon portions, indicating they are encoded independently at different gene positions. In addition, analysis of the two proteins has shown differences in their respective amino acid sequences.
The first compound found to selectively inhibit MAO-B was (R)-N-xcex1-dimethyl-N-2-propynylbenzeethanamine, also known as L-(xe2x88x92)-N-xcex1-N-2-propynylphenethylamine, (xe2x88x92)-deprenil, L-(xe2x88x92)-deprenil, R-(xe2x88x92)-deprenyl, or selegiline. Selegiline has the following structural formula: 
Selegiline is the active ingredient of a human drug product and is known in the art as a component of a therapeutic package. In particular, see Physicians Desk Reference (1995) pp. 2430-2432 (1995 PDR), describing Eldepryl(copyright) Tablets, manufactured by Somerset Pharmaceutical, Inc. and marketed by Sandoz, the active ingredient of which is selegiline. For example, the 1995 PDR describes a 5 mg selegiline hydrochloride tablet and further describes the manner in which selegiline-containing therapeutic packages are supplied for commercial use or sale. In particular, the 1995 PDR discloses that 5.0 mg Eldepryl Tablets are sold in xe2x80x9cNDC 39506-011-25 bottles of 60 tablets.xe2x80x9d
In commercial use, selegiline-containing therapeutic packages are labeled and otherwise indicated for use in Parkinsonian patients receiving levodopa/carbidopa therapy. The 1995 PDR cited above provides an example of the complete approved labeling that is employed in known therapeutic packages. Accordingly, known in the prior art are therapeutic packages providing one or more unit doses of selegiline as an active ingredient thereof, supplied in a finished pharmaceutical container that contains said unit doses, and further contains or comprises labeling directing the use of said package in the treatment of a human disease or condition as described above.
In addition to Parkinson""s disease, other diseases and conditions for which selegiline is disclosed as being useful include: drug withdrawal (WO 92/21333, including withdrawal from psychostimulants, opiates, narcotics, and barbiturates); depression (U.S. Pat. No. 4,861,800); Alzheimer""s disease and Parkinson""s disease, particularly through the use of transdermal dosage forms, including ointments, creams and patches; macular degeneration (U.S. Pat. No. 5,242,950); age-dependent degeneracies, including renal function and cognitive function as evidenced by spatial learning ability (U.S. Pat. No. 5,151,449); pituitary-dependent Cushing""s disease in humans and nonhumans (U.S. Pat. No. 5,192,808); immune system dysfunction in both humans (U.S. Pat. No. 5,387,615) and animals (U.S. Pat. No. 5,276,057); age-dependent weight loss in mammals (U.S. Pat. No. 5,225,446); schizophrenia (U.S. Pat. No. 5,151,419); and various neoplastic conditions including cancers, such as mammary and pituitary cancers (see, e.g., Thyagarajan et al. (1995)). PCT published application WO 92/17169 discloses the use of selegiline in the treatment of neuromuscular and neurodegenerative disease and in the treatment of CNS injury due to hypoxia, hypoglycemia, ischemic stroke or trauma. In addition, the biochemical effects of selegiline on neuronal cells have been extensively studied (e.g., see Tatton, et al., xe2x80x9cSelegiline Can Mediate Neuronal Rescue Rather than Neuronal Protection,xe2x80x9d Movement Disorders 8 (Supp. 1):S20-S30(1993); Tatton, et al., xe2x80x9cRescue of Dying Neurons,xe2x80x9d J. Neurosci. Res. 30:666-672 (1991); and Tatton, et al., xe2x80x9c(xe2x88x92)-Deprenyl Prevents Mitochondrial Depolarization and Reduces Cell Death in Trophically-Deprived Cells,xe2x80x9d 11th Int""l Symp. on Parkinson""s Disease, Rome, Italy, March 26-30, 1994.)
Selegiline is known to be useful when administered to a subject through a wide variety of routes of administration and dosage forms. For example U.S. Pat. No. 4,812,481 (Degussa AG) discloses the use of concomitant selegiline-amantadine in oral, peroral, enteral, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intraarterial, intracardial, intramuscular, intraperitoneal, intracutaneous, and subcutaneous formulations. U.S. Pat. No. 5,192,550 (Alza Corporation) describes a dosage form comprising an outer wall impermeable to selegiline but permeable to external fluids. This dosage form may have applicability for the oral, sublingual or buccal administration of selegiline. Similarly, U.S. Pat. No. 5,387,615 discloses a variety of selegiline compositions, including tablets, pills, capsules, powders, aerosols, suppositories, skin patches, parenterals, and oral liquids, including oil-aqueous suspensions, solutions, and emulsions. Also disclosed are selegiline-containing sustained release (long acting) formulations and devices.
Although a highly potent and selective MAO-B inhibitor, selegiline""s practical use is circumscribed by its dose-dependent specificity for MAO-B, and the adverse pharmacology of selegiline metabolites generated after administration.
The selectivity of selegiline in the inhibition of MAO-B is important to its safety profile following oral administration. Inhibition of MAO-A in peripheral sites (such as, for example, gastric epithelium, liver parenchyma, and sympathetic neurons) may cause toxic side effects by interfering with the metabolism of tyramine. Tyramine is normally metabolized in the gastrointestinal tract by MAO-A but when MAO-A is inhibited, tyramine absorption is increased following consumption of tyramine-containing foods such as cheese, beer, herring, etc. This results in the release of catecholamines which can precipitate a hypertensive reaction, producing the xe2x80x9ccheese effect.xe2x80x9d This effect is characterized by Goodman and Gilman as the most serious toxic effect associated with MAO-A inhibitors.
Selegiline is metabolized into its N-desmethyl analog (and their various potentially harmful methamphetamines). Structurally, this N-desmethyl metabolite is the R(xe2x88x92) enantiomeric form R(xe2x88x92)DMS of a secondary amine of the formula: 
Heretofore, R(xe2x88x92)DMS was not known to have pharmaceutically useful MAO-related effects, i.e., potent and selective inhibitory effects on MAO-B. In the course of determining the usefulness of R(xe2x88x92)DMS for the purposes of the present invention, the MAO-related effects of R(xe2x88x92)DMS were more completely characterized. This characterization has established that desmethylselegiline has exceedingly weak MAO-B inhibitory effects and no advantages in selectivity with respect to MAO-B compared to selegiline.
For example, the present characterization established that selegiline has an IC50 value against MAO-B in human platelets of 5xc3x9710xe2x88x929 M whereas R(xe2x88x92)DMS has an IC50 value of 4xc3x9710xe2x88x927 M, indicating the latter is approximately 80 times less potent as an MAO-B inhibitor than the former. Similar characteristics can be seen in the following data measuring inhibition of MAO-B and MAO-A in rat cortex mitochondrial-rich fractions:
As is apparent from the above table, selegiline is approximately 128 times more potent as an inhibitor of MAO-B relative to MAO-A, whereas R(xe2x88x92)DMS is about 97 times more potent as an inhibitor of MAO-B relative to MAO-A. Accordingly, R(xe2x88x92)DMS appears to have an approximately equal selectivity for MAO-B compared to MAO-A as-selegiline, albeit with a substantially reduced potency.
Analogous results are obtained in rat brain tissue. Selegiline exhibits an IC50, for MAO-B of 0.11xc3x9710xe2x88x927 M whereas R(xe2x88x92)DMS has an IC50 value of 7.3xc3x9710xe2x88x927 M, indicating R(xe2x88x92)DMS is approximately 70 times less potent as an MAO-B inhibitor than selegiline. Both compounds exhibit low potency in inhibiting MAO-A in rat brain tissue, 0.18xc3x9710xe2x88x925 for selegiline, 7.0xc3x9710xe2x88x925 for R(xe2x88x92)DMS. Thus, in vitro R(xe2x88x92)DMS is approximately 39 times less potent than selegiline in inhibiting MAO-A.
Based on its pharmacological profile as set forth above, R(xe2x88x92)DMS as an MAO-B inhibitor provides no advantages in either potency or selectivity compared to selegiline. Indeed, the above in vitro data suggest that use of R(xe2x88x92)DMS as an MAO-B inhibitor requires on the order of 70 times the amount of selegiline.
The potency of R(xe2x88x92)DMS as an MAO-B inhibitor in vivo has been reported by Heinonen, E. H., et al. (xe2x80x9c[R(xe2x88x92)Desmethylselegiline, a metabolite of selegiline, is an irreversible inhibitor of MAO-B in human subjects,xe2x80x9d referenced in Academic Dissertation xe2x80x9cSelegiline in the Treatment of Parkinson""s Disease,xe2x80x9d from Research Reports from the Department of Neurology, University of Turku, Turku, Finland, No. 33 (1995), pp. 59-61). According to Heinonen, R(xe2x88x92)DMS in vivo has only about one-fifth the MAO-B inhibitory effect of selegiline, i.e., a dose of 10 mg of desmethylselegiline would be required for the same MAO-B effect as 1.8 mg of selegiline. In rats, Borbe reported R(xe2x88x92) DMS to be an irreversible inhibitor of MAO-B, with a potency about 60 fold lower than selegiline in vitro and about 3 fold lower ex vivo (Barbe, H. O., J Neural Trans. (Suppl.):32:131 (1990)). Thus, all previous investigators have reported data indicating that R(xe2x88x92)DMS is a less-preferred, less effective MAO inhibitor than selegiline and therefore a less desirable therapeutic compound.
The present invention is based upon the surprising discovery that R(xe2x88x92)DMS and its enantiomer S(+)DMS, having the following structure: 
are particularly useful in providing selegiline-like effects in subjects, notwithstanding dramatically reduced MAO-B inhibitory activity and an apparent lack of enhanced selectivity for MAO-B compared to selegiline. It has been discovered that R(xe2x88x92)DMS, S(+)DMS, and combinations such as racemic mixtures of the two provide a more advantageous way of obtaining selegiline therapeutic effects in selegiline-responsive diseases or conditions. This is particularly true for diseases or conditions characterized by neoplastic cells such as, for example, cancerous cells, or cells that proliferate in an unregulated manner.
Thus, the present invention provides novel pharmaceutical compositions in which R(xe2x88x92)DMS, S(+)DMS, or a combination, such as a racemic mixture, of the two is employed as the active ingredient. Also provided are novel therapeutic methods involving the administration of such compositions. More specifically, the present invention provides:
(1) A pharmaceutical composition comprising an amount of R(xe2x88x92)DMS, S(+)DMS, or a combination of the two, such that one or more unit doses of said composition
(1) A pharmaceutical composition comprising an amount of R(xe2x88x92)DMS, S(+)DMS, or a combination of the two, such that one or more unit doses of said composition administered on a periodic basis is effective to treat one or more neoplastic diseases or conditions in a subject to whom said unit dose or unit doses are administered. This composition may be formulated for non-oral or oral administration.
(2) A method of treating a neoplastic condition in a subject, such as a mammal, which comprises administering to said mammal R(xe2x88x92)DMS, S(+)DMS, or a combination of the two, in a dosage regimen effective to produce a selegiline therapeutic effect, such as a daily dose, administered in a single or multiple dosage regimen of at least about 0.0015 mg, calculated on the basis of the free secondary amine, per kg. of the mammals body weight.
(3) A transdermal delivery-system for use in treating a neoplastic condition in a mammal which comprises a layered composite of one or more layers with at least one layer including an amount of R(xe2x88x92)DMS, S(+)DMS, or a combination of the two sufficient to supply a daily transdermal dose of at least about 0.0015 mg of the free secondary amine, per kg of the mammal""s body weight; and
(4) A therapeutic package for dispensing to, or for use in dispensing to, a patient being treated for a neoplastic disease or condition. The package contains one or more unit doses, each such unit dose comprising an amount of R(xe2x88x92)DMS, S(+)DMS or a combination of the two, such that periodic administration is effective in treating the patient""s neoplastic disease or condition. The therapeutic package also comprises a finished pharmaceutical container containing the unit doses of R(xe2x88x92)DMS, S(+)DMS, or combination thereof, and further containing or comprising labeling directing the use of the package in the treatment of the neoplastic disease or condition. The unit doses may be adapted for oral administration, e.g. as tablets or capsules, or may be adapted for non-oral administration.
(5) A method of dispensing R(xe2x88x92)DMS, S(+)DMS, or a combination of the two, to a patient being treated for a neoplastic disease or condition. The method comprises providing patients with a therapeutic package having one or more unit doses of desmethylselegiline, ent-desmethylselegiline or a mixture of the two, in an amount such that periodic administration to the patient is effective in treating their selegiline-responsive neoplastic disease or condition. The package also comprises a finished pharmaceutical container containing the desmethylselegiline, ent-desmethylselegiline, or a mixture of the two, and having labeling directing the use of the package in the treatment the selegiline-responsive neoplastic disease or condition. The unit doses in the package may be adapted for either oral or non-oral.
Preferred embodiments of the present disclosure are methods for obtaining a selegiline therapeutic effect in a patient with a neoplastic disease or condition, by administering to the patient R(xe2x88x92)DMS, S(+)DMS, or a mixture of R(xe2x88x92)DMS and S(+)DMS. Preferably the patient is a mammal, more preferably a human or a domesticated animal. The R(xe2x88x92)DMS, S(+)DMS, or a mixture of both enantiomers is preferably administered in a dosage regimen effective to suppress or inhibit, in whole or in part, occurrence, reoccurrence, or progression of the neoplastic disease or condition. In preferred embodiments, R(xe2x88x92)DMS or S(+)DMS is administered in a substantially enantiomerically pure form. In other preferred embodiments, R(xe2x88x92)DMS and/or S(+)DMS are administered as the free base or as an acid addition salt. Preferably the acid addition salt is hydrochloride salt. In yet another preferred embodiment, the neoplastic disease or condition treated by administering R(xe2x88x92)DMS, S(+)DMS, or a combination of the two, is a mammary tumor or a pituitary tumor.
In another preferred embodiment of the present disclosure, R(xe2x88x92)DMS, S(+)DMS, or a mixture of both enantiomers is administered at a daily dose of between about 0.02 mg/kg and about 5.0 mg/kg, more preferably at a daily dose of between about 0.6 mg/kg and about 0.8 mg/kg, calculated on the basis of the free secondary amine. In preferred embodiments of the present disclosure, the R(xe2x88x92)DMS, S(t)DMS, or a combination of the two is administered by an oral route of administration, or a non-oral route of administration. Non-oral routes of administration preferably include sublingual, buccal, parenteral, or transdermal administration. In a preferred embodiment, R(xe2x88x92)DMS, S(+)DMS, or a combination of the two is administered by a transdermal patch.
Another preferred embodiment of the present disclosure is a pharmaceutical composition that includes R(xe2x88x92)DMS, S(+)DMS, or a mixture of R(xe2x88x92)DMS and S(+)DMS, as well as a second therapeutic agent useful in the treatment of a neoplastic disease or condition. In a preferred embodiment, one or more therapeutic agents are included in the pharmaceutical composition. In another preferred embodiment, the R(xe2x88x92)DMS, S(+)DMS, or mixture of R(xe2x88x92)DMS and S(+)DMS, and the second therapeutic agent, are present in the pharmaceutical composition in an amount such that one or more unit doses of the composition are effective to suppress or inhibit, in whole or in part, progression of the neoplastic disease or condition. In other preferred embodiments, R(xe2x88x92)DMS and/or S(+)DMS are administered as the free base or as an acid addition salt. Preferably the acid addition salt is hydrochloride salt. In yet another preferred embodiment, the neoplastic disease or condition treated by a pharmaceutical composition with R(xe2x88x92)DMS, S(+)DMS, or a combination of the two, and a second therapeutic agent, is a mammary tumor or a pituitary tumor. In another preferred embodiment of the present disclosure, the second therapeutic agent is an anti-neoplastic agent or a chemotherapeutic agent. Preferably the anti-neoplastic agent is tamoxifen, cisplatin, paclitaxel, or methotrexate. In a preferred embodiment the second therapeutic agent is a radiation implant.
In other preferred embodiments, the R(xe2x88x92)DMS, S(+)DMS, or combination of the two enantiomers in a unit dose of the pharmaceutical composition is between about 0.02 and about 5.0 mg/kg, more preferably between about 0.6 and about 0.8 mg/kg, calculated on the basis of the free secondary amine. In another preferred embodiment, the R(xe2x88x92)DMS, S(+)DMS, or combination of the two enantiomers in a unit dose of the pharmaceutical composition is between about 1.0 mg and about 100.0 mg, more preferably between about 5.0 mg and about 10.0 mg. In yet another preferred embodiment, the pharmaceutical composition is for oral administration, for non-oral administration, or for transdermal administration. In a preferred embodiment the pharmaceutical composition is a transdermal patch.
Preferred embodiments of the present disclosure are also directed to methods for obtaining a selegiline therapeutic effect in a patient with a neoplastic disease or condition, by administering to the patient a pharmaceutical composition that includes R(xe2x88x92)DMS, S(+)DMS, or a mixture of R(xe2x88x92)DMS and S(+)DMS, as well as a second therapeutic agent useful in the treatment of a neoplastic disease or condition. In another preferred embodiment, one or more unit doses of the pharmaceutical composition are effective to suppress or inhibit, in whole or in part, occurrence, reoccurrence, or progression of the neoplastic disease or condition. Other preferred embodiments of the present disclosure are directed to methods for obtaining a selegiline therapeutic effect in a patient with a neoplastic disease or condition, by administering to the patient R(xe2x88x92)DMS, S(+)DMS, or a mixture of R(xe2x88x92)DMS and S(+)DMS in combination with a second therapy useful in the treatment of a neoplastic disease or condition, in a dosage regimen effective to suppress or inhibit, in whole or in part, occurrence, reoccurrence, or progression of the neoplastic disease or condition. Preferably the second therapy is chemotherapy or radiation.